The present invention relates to a process for making bicalutamide and/or its intermediates using a sulfinic acid salt and to certain intermediate compounds useful in the production of bicalutamide.
Bicalutamide is the common name for the compound 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline, and is represented by the formula (1): 
Bicalutamide is a non-steroidal antiandrogen pharmaceutically active agent that is generally used in the treatment of prostate cancer; i.e., for androgen deprivation treatment, although other androgen dependent conditions may also be treated. Bicalutamide is commercially available in a pharmaceutical composition as a racemate under the brand name CASODEX(copyright) (Astra-Zeneca). The R-stereoisomer of bicalutamide has been proposed in U.S. Pat. No. 5,985,868 as being more beneficial than the racemate.
U.S. Pat. No. 4,636,505 teaches a genus of acylanilides including bicalutamide as having antiandrogen activity. Three processes are generically put forth for making the various acylanilides. The first process comprises reacting an acid of the formula HO2Cxe2x80x94CR5R6xe2x80x94A1xe2x80x94X1xe2x80x94A2xe2x80x94R7 or a reactive derivative thereof with an aniline compound of a specified formula. The substituents R5 and R6 include hydroxyl and methyl groups; A1 includes methyl, ethyl and ethylidene; X1 includes oxygen, sulfur, sulfinyl, sulfonyl, imino, and methylimino; A2 can be a direct link; and R7 includes substituted phenyl. This process is not exemplified in making bicalutamide in the U.S. Pat. No. 4,636,505. Instead, the examples only show this process for making thio or oxy derivatives wherein X1 is sulfur or oxygen. However, the sulfur is taught to be oxidized to sulfinyl or sulfonyl and thus bicalutamide can be produced with subsequent oxidation by this general reaction according to the following reaction scheme: 
wherein the thio derivative (C) is then oxidized to produce bicalutamide (i.e., sulfur (S) becomes sulfonyl (SO2)). The starting compound (A) having X as a methoxy group was prepared by opening the epoxy-ring of methyl 2,3-epoxy-2-methylpropionate (D) by reacting the same with p-fluorothiophenol (E) as represented below: 
The second process likewise uses a thiophenol compound in order to make a thio analogue of bicalutamide. The process condenses an appropriate thiophenol such as p-fluorothiophenol (E) with an appropriate epoxy-anilide such as (F) to make a thio-analogue of, inter alia, bicalutamide (C). Again, the thio analogue must be oxidized to obtain a sulfonyl linking group in order to make bicalutamide. 
The starting epoxy-anilide (F) was prepared by condensation of the aniline (B) with methacryloylchloride and epoxidation of the so obtained acryl-anilide (G) 
U.S. Pat. No. 4,636,505 also suggests that the compound (F) may be replaced in this process by an activated hydroxy-compound (H) wherein L is a leaving group: 
However, no working example of a process employing a compound of a general formula (H) was provided in the U.S. Pat. No. 4,636,505.
The third process disclosed in U.S. Pat. No. 4,636,505 comprises reacting an organometallic compound of the formula R7xe2x80x94A2xe2x80x94X1xe2x80x94A1xe2x80x94M, where M is a metal radical, with an appropriate aniline derivative such as: 
to form the corresponding acylanilide. No example of this process is set forth in the U.S. Pat. No. 4,636,505.
Consistent with the examples, U.S. Pat. No. 4,636,505 teaches that when X1 is desired to be sulfinyl or sulfonyl, the compound may be prepared by oxidizing the corresponding thio-acylanilide compound. Based on these teachings and examples, U.S. Pat. No. 4,636,505 can be seen as teaching the use of a thiophenol of compound (E) above to make bicalutamide by first forming the thio-acylanilide analogue compound (C) followed by oxidation to bicalutamide. The thiophenol can be reacted to form the hydroxy acid of compound (A) which is then subsequently reacted with an aniline compound, or, the thiophenol can be reacted with an acylanilide compound (F) to form the thio bicalutamide analogue.
Other synthetic routes have been proposed for making bicalutamide, especially optically pure bicalutamide. In J. Med. Chem. 885-887 (1988) and J. Med. Chem. 31, 954 (1988) a starting compound of the above compound (H) wherein L is Br in rigid conformation was prepared by bromination of N-methacrylamide of natural (S)-proline (by asymmetric bromolactonisation according to Terashima) to form the cyclic compound (L) 
which was hydrolyzed to yield the (S)-isomer of 2-hydroxy-3-bromoisobutyric acid (N). 
This was coupled with the aniline (B) to yield the substituted bromohydrine (H) (L=Br) which, after reaction with p-fluorothiophenol (E), provided for thio-bicalutamide (C), however with undesired (S) conformation.
In U.S. Pat. No. 6,019,957, the similar synthesis of (R)-bicalutamide via a iodinated analogue of (H) (i.e. with L=I) was described, starting with (R)-proline. The R-proline provides for the desired conformation. However, it is the unnatural proline isomer and thus highly expensive.
WO01/00608 discloses another route for making racemic or optically pure bicalutamide and also provides a summary of the above processes. In this document, the three routes from U.S. Pat. No. 4,636,505 are set forth for making bicalutamide as FIGS. 1-3. Another route based on the cyclized N-methacrylamide of proline is shown in FIG. 4. The fifth and purportedly inventive route forms a compound (H) where L is xe2x80x94OSO2xe2x80x94R via an amidation reaction of the aniline (B) with a cyclic sulfite-ester of 2,3-dihydroxyisobutyric acid chloride (M) 
The reaction can produce racemic or optically pure bicalutamide depending on the optical purity of the starting 2,3-dihydroxy-2-methyl-propionic acid used to make the cyclic sulfite-ester (M). According to FIG. 5, the compound (H) is reacted with the sodium salt of p-fluorothiophenol to make the thio analogue of bicalutamide (C) followed by oxidation thereof to produce bicalutamide.
WO 01-28990 also describes several methods for how to obtain bicalutamide, optionally via a stereoselective synthesis of the compound (A). The processes include the use of an oxiran ring as in U.S. Pat. No. 4,636,505, a cyclized proline derivative similar to the above articles, or citramalic acid. The later process starts from natural S-citramalic acid which is firstly protected by bromal and brominated upon decarboxylation to form a compound (K). 
This compound is condensed with p-fluorothiophenol (E) with subsequent hydrolysis of the protective group, resulting in a compound (A), which is then amidated with the aniline (B) and the formed compound (C) finally oxidized to produce bicalutamide.
The fully elucidated processes for making bicalutamide in the above-mentioned documents all use a p-fluorothiophenol compound, albeit with different reaction partners, to provide a thio linkage which is oxidized in a final step to form the sulfonyl linkage required for bicalutamide. But p-fluorothiophenol is a toxic and unpleasant smelling compound making it somewhat difficult to work with, especially on a large scale.
The present invention relates to the discovery that a p-fluorobenzenesulfinic acid salt can be successfully used as a reagent in the synthesis of bicalutamide and/or the intermediates therefor. Accordingly, a first aspect of the present invention relates to a process for making bicalutamide, which comprises reacting a compound of formula (2) 
wherein Z represents a cation, with a suitable reaction partner to form a bicalutamide of formula (1): 
or a non-bicalutamide product and, if the reacting step produces a non-bicalutamide product, then converting the non-bicalutamide product to a bicalutamide of formula (1). Z is preferably a cation selected from alkali metals, magnesium halides, and ammoniums, and typically is a sodium cation; i.e. sodium p-fluorobenzenesulfinate. The bicalutamide can be obtained in racemic form or enriched by a single optical isomer.
Another aspect of the invention relates to a process, which comprises reacting a compound of formula (2) 
wherein Z represents a cation; with a compound of formula (3) 
wherein A represents OR, in which R is a hydrogen, a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, or a benzyl group; or A represents an aniline derivative of the formula: 
Y represents a leaving group and X represents hydrogen or X and Y join together to form a 3-6-membered heterocyclic ring or X and A join together to form a 5- to 10-membered fused or unfused heterocyclic ring with the proviso that if a ring nitrogen is present, it may be substituted by a 3-trifluoromethyl-4-cyano-phenyl group; to form a compound of the formula (4): 
wherein A and X have the same meaning as in formula (3). When A represents the aniline derivative, the compound of formula (4) is a bicalutamide compound. When A is hydrogen or otherwise represents or is converted to a leaving group, the compound of formula (4) can be reacted with an amine derivative to form a bicalutamide compound of formula (1).
A further aspect of the present invention relates to a compound of the formula (4): 
wherein A represents OR, in which R is a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, or a benzyl group; X represents hydrogen or X and A join together to form a 5- to 10-membered fused or unfused heterocyclic ring with the proviso that if a ring nitrogen is present, it may be substituted by a 3-trifluoromethyl-4-cyano-phenyl group. These intermediates are useful in making bicalutamide.
The present invention uses a fluorobenzenesulfinate of formula (2) in making bicalutamide or intermediates thereof. 
Z represents a cation and thus is not covalently bonded to the oxygen atom. However, for simplicity, the charges are not shown on the oxygen or cation. Preferably the cation is selected from alkali metals, magnesium halides, and ammoniums. For example, sodium, potassium, magnesium chloride, magnesium bromide, ammonium, dialkylammonium having 1-4 carbon atoms in each alkyl group, are possible cations. Sodium p-fluorobenzenesulfinate, the compound of formula (2) when X is a sodium, is a particularly useful reagent compound in forming bicalutamide or its intermediates.
All of the p-fluorobenzenesulfinic acid compounds of formula (2), and particularly a sodium salt of p-fluorobenzenesulfinic acid, may be prepared by various methods known in the art. One such process is based on a method described by Oxley et al., J. Chem. Soc. 1946, 763 for analogous compounds. The process comprises reaction of p-fluorobenzene sulfonylchloride with sodium sulfite and sodium bicarbonate in a suitable solvent, e.g. in water. Alternatively, p-fluorobenzene sulfonylchloride may be converted to the p-fluorobenzenesulfinic acid by reduction/dehalogenation by sodium borohydride as described in WO 00-58279. Furthermore, a Grignard reagent prepared from p-fluorophenyl bromide and magnesium can be quenched with sulfur dioxide. The resulting bromomagnesium salt of p-fluorobenzenesulfinic acid may be used in crude state or can be converted to the free acid or to an alkali metal salt thereof. The free acid, however formed, can be converted to any of the salt compounds of formula (2).
The p-fluorobenzenesulfinic acid compounds of formula (2) can be used to make bicalutamide, either directly, that is as the last synthetic step, or indirectly, that is by making an intermediate that is subsequently reacted one or more times to form bicalutamide. In this regard, the p-fluorobenzenesulfinates of the present invention can be used instead of the conventional p-fluorothiophenol in any of the above-described reaction schemes; e.g., the three processes generally described in U.S. Pat. No. 4,636,505, the five processes described in the figures of WO01/00608, etc., but is not limited thereto. In short, any reaction scheme that uses the p-fluorobenzenesulfinate of formula (2) in the formation of bicalutamide is included within the present invention. By using the p-fluorobenzenesulfinate of formula (2) to provide the sulfonyl linkage in bicalutamide, and typically the entire p-fluorobenzenesulfonyl terminal group, the usual prior art oxidation of a thio linkage can be avoided. Moreover, the compounds of formula (2) are less toxic, less odiferous and easier to handle than the conventionally used p-thiophenol.
Indeed, it is surprising that a p-fluorobenzenesulfinic acid salt could be used in place of p-fluorothiophenol because of the differences in chemistry. Specifically, an arene sulfinic acid, contrary to a thiophenol, has two reactive centers: the sulfur atom and the oxygen atom. It is apparent that the substitution on the sulfur atom is the desired reaction for purposes of making bicalutamide, however, general knowledge teaches that a sulfinic acid may also undergo substitutions on the oxygen (esterification reactions). Furthermore, thiophenols are also stronger nucleophiles than sulfinic acids. Nonetheless, the reaction can proceed using the p-fluorobenzenesulfinic acid salts of the formula (2). It is preferred that the reaction conditions are adjusted to suppress the O-substitution and/or support the S-substitution and to support nucleophilic substitution. In particular, the preferred environment for reaction of p-fluorobenzenesulfinic acid compound comprises a biphasic reaction system. Such a two-phase system generally comprises water and a water-immiscible solvent, optionally with the aid of a phase-transfer catalyst. Alternatively, the reaction is carried out in a lower alcohol solvent in the presence of a strong acid. The lower alcohol generally has 2 to 6 carbon atoms and is typically ethanol, propanol including isopropanol, butanol or a combination of these. A xe2x80x9cstrong acidxe2x80x9d is an acid that completely dissociates in an aqueous solution such as hydrochloric acid or sulfuric acid, the latter being preferred.
The bicalutamide prepared by the use of a p-fluorobenzenesulfinate of formula (2) is a bicalutamide of formula (1): 
Because bicalutamide has a chiral carbon it exists in two enantiomeric forms, namely as an R- and S- optical isomer. The bicalutamide of formula (1) can be racemic or an enriched optical isomer including a pure or substantially pure optical isomer. In this context, xe2x80x9cenrichedxe2x80x9d means at least 65% optically pure, more preferably at least 75% optically pure and typically at least 80% optically pure. xe2x80x9cSubstantially purexe2x80x9d means at least 95% optically pure, preferably at least 99% optically pure. The enriched optical isomer is preferably the (R)-bicalutamide. The enriched optical isomer can be obtained by using optically enriched reaction partners as explained in more detail below, or by separation methods after the formation of a racemic bicalutamide. Suitable separation methods are well known in the prior art and include fractional crystallization techniques and column chromatography among others.
Various reaction partners can be used to form bicalutamide using the p-fluorobenzenesulfinate of formula (2). A preferred reaction partner is a compound of formula (3), which can be represented by the following reaction: 
In formula (3), A represents OR, in which R is a hydrogen, a C1-C6 alkyl, a C3-C6 cycloalkyl, a phenyl, or a benzyl group; or A represents an aniline derivative of the formula: 
R preferably represents hydrogen, methyl, ethyl, propyl including iso-propyl, butyl including iso- and tert- butyl, or phenyl. Y represents a leaving group and X represents hydrogen. Further the formula can optionally be cyclized such that X and Y join together to form a 3- to 6-membered heterocyclic ring or X and A join together to form a 5- to 10-membered fused or unfused heterocyclic ring. If the ring formed by X and A contains a ring nitrogen, then the ring nitrogen may be substituted by a 3-trifluoromethyl-4-cyano-phenyl group. In formula (4), X and A have the same definitions as in formula (3). In rare circumstances, it is possible that the A group in formula (3) is not the same as the A group in formula (4), albeit both groups are within the definition of A. The same is true for X. For example, if X and A in formula (3) form a ring, it is contemplated that the ring may open during the reaction with the compound of formula (2) thereby making X a hydrogen in the formula (4) compound. However, normally X and A have the same value in both formulae (3) and (4).
Suitable leaving groups for Y are those groups that facilitate nucleophilic substitution by the p-fluorobenzenesulfinate of formula (2), i.e., provide a sufficiently activated reaction partner. Preferred leaving groups are a halogen such as chloro, bromo, or iodo, or a group of the formula xe2x80x94OS(O)2xe2x80x94R2, wherein R2 represents a hydroxyl group, a C1-C4 alkyl group, a phenyl group, or an alkyl-substituted phenyl group. Preferably R2 represents methyl, ethyl, or methyl substituted phenyl. More preferred are iodine, chlorine, bromine, methanesulfonyloxy or toluenesulfonyloxy.
The ring formed by X and Y is a 3- to 6-membered heterocyclic ring. Because the ring is completed by the joining together of X and Y, the ring necessarily contains a ring oxygen bonded to a ring carbon. Further this ring carbon has a methyl substituent. The ring opens upon reaction with the p-fluorobenzenesulfinate of formula (2) to form a compound of formula (4). The ring preferably is comprised of carbons and one or more oxygens, optionally with a ring sulfur atom. Preferred rings are known in the art for synthesizing bicalutamide or related acylanilides using thiophenol compounds; for example, an oxiran ring or a cyclic sulfate ester. Specifically, these rings can be represented as follows: 
wherein the * indicates the location of the bond to the carbonyl group of formula (3). The oxiran ring is the most preferred ring formed by Y and X.
In making bicalutamide, the aniline moiety can be present before the reaction with the compound of formula (2), i.e., A is the above-shown aniline derivative, or it can be added afterwards, i.e. A is either the OR group or together with X forms the 5- to 10-membered fused or unfused heterocyclic ring. When A is the aniline derivative, then the compound of formula (4) is a bicalutamide of formula (1). When A is not the aniline derivative, then the compound of formula (4) is further reacted to add the aniline moiety and form bicalutamide. This can be done directly by subjecting the compound of formula (4), especially when A is OH, to an amidation reaction with an amine, preferably an amine of formula (11): 
Alternatively, the compound of formula (4) may be converted to a compound of formula (4.1): 
wherein L represents a leaving group for an amidation reaction, and then carrying out the amidation reaction with the above-mentioned amine compound of formula (11) to form a bicalutamide of formula (1). L preferably represents a halogen such as chloro, bromo, or iodo, or a group of the formula xe2x80x94OS(O)2xe2x80x94R2, wherein R2 represents a hydroxyl group, a C1-C4 alkyl group, a phenyl group, or an alkyl-substituted phenyl group. Preferably R2 represents methyl, ethyl, or methyl substituted phenyl. More preferred are iodine, chlorine, bromine, methanesulfonyloxy or toluenesulfonyloxy. In either event, the amidation reaction conditions may generally be similar to those as used for making the thio-analogues of bicalutamide in EP 100172.
If desired and whenever produced in a racemic form, the compounds of formula (4) may be resolved into single enantiomers such as by using methods analogous to those disclosed in WO 01-34563.
The 5- to 10-membered heterocyclic ring formed by A and X is preferably hydrolyzable to form a compound of formula (4) where A is an OR group or a compound of formula (4.1). More preferably the ring provides the methyl and hydroxyl groups in an optically enriched form so that optically enriched bicalutamide can be obtained. Preferred are rings formed by cyclizing proline derivatives or citramalic acid or its derivatives. Specific compounds of formula (3) where A and X have joined together include compounds of formula (3A), (3B), and (3C): 
Each of the above compounds can be reacted with p-fluorobenzenesulfinate of formula (2), Y being a leaving group. The resulting compound can be hydrolyzed to open the ring. In the case of formula (3A) and (3B), the ring open compound is either a compound of formula (4.1) or converted to such a compound and then subjected to amidation as described above to form a bicalutamide of formula (1). In the case of formula (3C), hydrolyzing the ring results in a bicalutamide of formula (1) as the aniline moiety is already present.
The compounds of formula (4) where A is the group OR but R does not include hydrogen or A and X form the above-mentioned ring, are useful intermediates and form a particular aspect of the present invention.
The invention will be further described with reference to several compounds and intermediates for the compounds of formula (3) wherein A represents the aniline derivative, (formula (5) series) and several compounds and intermediates for compounds of formula (3) wherein A does not represent the aniline derivative (formula (6) series). The first group of processes uses the compound (2) to provide directly a bicalutamide of formula (1), essentially in one reaction step, as shown in the scheme: 
Useful reaction partners of general formula (5) comprise:
1. An Epoxy-amide Compound (5A) 
The compound of formula (5A) may be prepared, e.g., by a condensation of 5-amino-2-cyanobenzotrifluoride with methacryloylchloride, followed by epoxidation of the resulting amide (7) as shown below: 
An example of such process is disclosed in EP 100172. The reaction between 5-amino-2-cyanobenzotrifluoride and metacryloylchloride preferably proceeds in a dipolar aprotic solvent, such as N,N-dimethylacetamide. Crude metacroyl amide product (7) may be isolated in solid state and purified by common methods, e.g. by crystallization. The preferred solvent for crystallization is toluene.
The amide (7) may be epoxidated for instance by a peracid, e.g. m-chloroperbenzoic acid, in an inert solvent, or by hydrogen peroxide in a presence of acetic acid anhydride and a catalyst (such as wolframic acid or a heteropoly acid such as phosphomolybdenic acid).
The method, as described, provides the compound (5A) as a racemate. The enantiomerically enriched compound (5A) may be obtained e.g. by an asymmetric epoxidation or by a suitable chemical conversion of a chiral precursor, e.g. by a ring-closure of an enantiomerically enriched hydroxy-compound of formula (5C) discussed hereinafter by an alkali, e.g. potassium carbonate, in a suitable solvent, e.g. in methanol.
2. A Hydroxy-compound of General Formula (5B) 
wherein L is a suitable leaving group, for instance a halogen atom, preferably bromine or iodine, or an alkyl- or arylsulfonyloxy group, preferably methane sulfonyloxy group or p-toluenesulfonyloxy group. Preferred compounds for reaction with compound (2) are compounds (5B) wherein L is bromine or iodine.
A compound (5B) wherein L is halogen (a halohydrine), may be produced from the above amide of formula (7) by an addition reaction with a hypohalite, e.g., hypochlorite. Under such conditions, the obtained compound (5B) is a racemate.
This halohydrine however could be prepared also by opening the oxiran ring of the epoxy-compound (5A) by a hydrohalic acid.
The halohydrine (5B, L=bromine) in rigid conformation may be prepared according to a method described in J.Med.Chem.31, 885-887 (1988) or U.S. Pat. No. 6,019,957.
Compounds of formula (5B), wherein L is alkyl- or arylsulfonyloxy group, are less reactive for direct reaction with (2). However, they may be transformed to corresponding bromo- or iodo analogues, e.g. by treatment with an alkali metal halide, e.g. by sodium iodide. Alternatively, they may be transformed into the epoxide compound (5A) by a treatment with a base, e.g. by sodium carbonate.
The compounds (5B) wherein L=RSO2Oxe2x80x94 group, may prepared by opening the oxiran ring of the epoxy-compound (5A) by a corresponding sulfonic acid Rxe2x80x94SO2OH. Alternatively, the compound (5B) wherein L=RSO2Oxe2x80x94 group, may also be prepared according to WO 01-00608 by an amidation reaction of the amine of formula (11) with a cyclic sulfo-ester of 2,3-dihydroxyisobutyric acid chloride. As a product of workup, a geminal-diol compound (5C) 
is formed and this compound is esterified by a corresponding alkyl- or aryl sulfonyl halide. The above geminal diol-compound (5C) is thus a useful intermediate for making other compounds of general formula (5), both in racemic or in enantiomerically enriched forms.
Apart of the process disclosed above, the compound of the formula (5C) may also be prepared by a dihydroxylation of the amide (7). To prepare the compound (5C) in a racemic form, the amide (7) is treated with a suitable oxidation agent, for instance by N-methylmorpholine-N-oxide (NMO) and osmium tetroxide in a suitable inert solvent. The reaction proceeds at ambient or close to ambient temperatures. Elaboration of the reaction mixture can proceed by conventional methods.
Alternatively, the compound (5C) may be prepared from the amide (7) by a dihydroxylation reaction according to Sharpless. In such a case, the compound (5C) is provided enriched by a single enantiomer. Sharpless dihydroxylation is described, e.g. in Johnson, R. A., Sharpless, K. B., Catalytic Asymmetric Synthesis, Ojima I. ed., Wiley-VCH, New York, 1993. In brief, the reaction employs a chiral oxidizing catalyst comprising either dihydroquinidine 1,4-phthalazinediyl diether (AD-mix-beta) or dihydroquinine 1,4-phthalazinediyl diether (AD mix alpha).
In another alternative, the compound (5C) may be produced by amidation of 2-methyl-2,3-dihydroxypropionic acid esters (compound of formula (6C) shown below). In such a case, the two hydroxy groups in (6C) are advantageously first protected by a suitable protective group, e.g. by means of an acetonide. The protected esterxe2x80x94a compound of formula (8)xe2x80x94
is first saponified to an acid (R=H) or to a salt, e.g. sodium salt (R=Na) and then amidated with the amine compound of formula (11) under conventional conditions, e.g. in the presence of an activated chloride, e.g. thionylchloride or oxalylchloride, to yield a protected amide (5E). 
The acetonide protective group is then removed under conventional conditions, yielding the desired (5C). As will be shown below, the starting compounds (6C) may be prepared in an enantiomerically enriched form. Accordingly, if such enriched starting material is used for the synthesis of compounds of formula (5C), such compounds are provided also enantiomerically enriched.
The racemic dihydroxy-compound (5C) may be subjected to optical resolution in order to obtain optically enriched reaction partners. Particularly suitable is a method employing optical resolution of a diastereomeric pair of chiral esters of the formula (5F) 
wherein W is an acyl moiety derived from an acid having its alpha-carbon chiral. An example of such chiral acid is (xe2x88x92)-camphanic acid. For instance, a mixture of enantiomers of (5C) reacts with (xe2x88x92) camphanic acid chloride and the obtained diastereomeric pair of compounds (5F) (W=(xe2x88x92)camphanoyl) is resolved by a conventional method, e.g. by a column chromatography, to fractions that are enriched by a single diastereomer. Any of the so obtained fractions is subjected to a hydrolysis, preferably alkaline hydrolysis, to remove the camphanoyl group. Thereby, an enantiomerically enriched compound (5C) is obtained.
3. A Cyclic Sulfate Compound (5D) 
Compound of formula (5D) may be prepared by oxidation of an intermediate cyclic sulfite-ester, which in turn may be prepared, e.g. from the geminal diol (5C) by a reaction with thionylchloride and an oxidation agent. The oxidation may be performed, e.g., by ruthenium (III) chloride/sodium periodate. The conversion of (5C) to (5D) may be performed in one process step.
The reaction between the above reactive compounds of the general formula (5), especially (5A), (5B), and (5D), and p-fluorobenzenesulfinic acid salt compound (2), whereby bicalutamide is obtained, preferably proceeds in a bi-phasic system comprising water and a water-immiscible solvent, preferentially in the presence of a phase-transfer catalyst. The water phase may also comprise a suitable buffer imparting the reaction pH from about 6.5 to about 7.5, e.g. a phosphate buffer. The buffer suppress undesired side reactions on the oxygen. The temperature of contact may be from ambient to reflux, the latter being preferred. The bicalutamide product concentrates in the organic phase and may be isolated therefrom and purified by ordinary methods.
In another variant, the p-fluorobenzenesulfinic acid salt (preferably sodium salt) reacts with the compound (5) in a lower alcohol, e.g. in ethanol. It is an advantage of this solvent that the sulfinate is soluble therein, at least at elevated temperature. A strong, non-nucleophilic acid is recommended to be present in small amounts to form a buffer with the sulfinate. The bicalutamide product crystallizes, together with inorganic salts, from the solvent and may be isolated by filtration. The inorganic salts may be removed by trituration of the solid residue by water.
If the starting compound (5) is used in an enantiomerically enriched form, then the resulting bicalutamide is accordingly enantiomerically enriched. It should be noted that (S) enantiomer of the compound (5) may provide (R)-bicalutamide and vice versa, dependent on the reaction conditions.
A second group of processes reacts p-fluorobenzenesulfinic acid salt of formula (2) with a suitable reaction partner to provide a compound of general formula (4) wherein A is not the aniline derivative. Instead, this compound (4) is used as an intermediate in further reaction to yield bicalutamide, e.g. by contacting it with the appropriate amine, preferably an amine compound of formula (11). If the reactivity of the group A is unsuitable for reaction with the amine, then the compound can be converted to a compound of formula (4.1) where in L is preferably a halogen atom, e.g. chlorine or bromine. The compounds of formula (4) may be produced and further used in a racemic form, or, alternately, as an enriched single optical isomer.
Suitable reaction partners of p-fluorobenzenesulfinates (2) in making compounds of formula (4) are compounds of general formula (6):
wherein A has the same meaning as in the case of compounds of formula (4) other than as the aniline derivative and D is either a leaving group such as halogen, e.g. bromine or iodine, an alkyl- or arylsulfonyloxy group such as methanesulfonyloxy group, or D represents a bond forming an oxirane or cyclic sulfate ring together with the OHxe2x80x94 group.
Useful reaction partners of formula (6) comprise:
1. An Epoxy-compound (6A) 
The compound (6A), wherein R=methyl, may be prepared by epoxidation of methyl methacrylate by a hydrogen peroxide, preferably under catalysis with a transition metal compound (e.g. wolframic acid). Alternatively, the epoxidation agent may be an organic peracid, for instance m-chloroperbenzoic acid. In this case, the reaction proceeds by heating in inert solvent, preferably under presence of a radical scavenger to increase the stability of the peracid, for instance bis (3-tert-butyl-4-hydroxy-5-methyl phenyl) sulfide.
In an optically active form, the compound (6A), wherein R=hydrogen, can be prepared also by oxidation of a chiral epoxy-alcohol (9), 
which in turn may be prepared by Sharpless asymmetric epoxidation of corresponding 2-methylallylalcohol (Gao et al. JACS 109, 5765-5780 [1987]. The ruthenium-catalyzed method of oxidation of (9) leading to (6A) has been suggested in J. Org. Chem. 60, 790-791 (1995).
2. A Hydroxy-compound (6B) 
wherein Y is a leaving group such as bromine or iodine atom. The compounds (6B) may be prepared by dihydroxylation of methacrylic acid esters (10) 
for instance by NMO/osmium tetroxide or potassium permanganate. The product of dihydroxylation reaction is a compound of formula (6C), 
which may be converted into the compounds (6B) by substitution the OHxe2x80x94 group by a halide. Depending on the conditions of the dihydroxylation reaction, the compound (6C) may be prepared either as a racemate or enriched by a single enantiomer. For instance, the Sharpless dihydroxylation as discussed above provides the compound (6C) in an enantiomerically enriched form. Accordingly, the desired compound (6B) may be obtained also enantiomerically enriched.
In this consequence, particularly interesting esters of methacrylic acid of the formula (10) are esters with a chiral alcohol, e.g. with L(xe2x88x92)-menthol. Such esters are represented by formula (10), wherein R is a chiral moiety derived from a chiral alcohol. After conventional dihydroxylation of such esters (e.g. by N-methylmorpholine oxide catalyzed by osmium tetroxide), the obtained racemic mixture of chiral dihydroxy esters (6C) may be easily resolved in the single diastereomers by conventional methods, e.g. by preparative column chromatography. Optionally, the menthol-moiety may then be removed by saponification or transesterification. Consequently, an enantiomerically enriched compound of formula (6B) may be obtained as well.
The compound (6B), wherein L is Br or I may be also prepared in enantiomerically pure form by the xe2x80x9cprolinexe2x80x9d method according to J. Med. Chem.885-887 (1988). As discussed above, the disadvantage of this method is that the cheap natural proline provides for the undesired (S) conformation of this compound.
3. A Cyclic Sulfate Ester (6D) 
The compound of formula (6D) wherein R is an ethyl group may be prepared by a reaction of ethyl 2-methylacrylate with phenyliodine(III)sulfate or oxodiphenyl-diiodine(III)sulfate as described by Zefirov et al. in Zh.Org.Khim. 22(8), 451 (1986).
The processes using any of the above reactive compounds of the general formula (6), especially (6A), (6B), and (6D), react with p-fluorobenzenesulfinic acid compound of the formula (2), particularly with sodium p-fluorobenzenesulfinate, under conditions of nucleophilic substitution. Reaction conditions may be similar as described above for the first general processes. In particular, the both reaction partners react in a bi-phasic system comprising water and a water-immiscible solvent, under presence of a phase-transfer catalyst. The reaction product can be converted by a bicalutamide compound, with or without isolation or modification of the leaving group, by amidation with the amine of formula (11) as explained above.
Apart from the compounds of formula (3), the p-fluorobenzenesulfinic acid salt (2) can be reacted with other suitable reaction partners to yield the desired compounds of formula (4). For instance, one such process starts from a compound of formula (3.1) 
wherein L is a leaving group such as halogen; preferred leaving group is bromine. The 3-bromo-2-methylpropene, i.e. a compound of formula (3.1), wherein L is bromine, is commercially available.
It may react with sodium p-fluorobenzenesulfinate in a suitable inert solvent, e.g. in ethanol, to yield an alkene compound of formula (12). Isolation and purification of the intermediate (12) may be preformed by standard methods, e.g. by column chromatography. In subsequent step, the compound (12) is oxidized by a suitable oxidation agent, e.g. by potassium permanganate in water, to yield a diol (13), which is further oxidized to yield the desired hydroxyacid compound of formula (4), wherein X is OH-group. 
The both oxidation reactions may be advantageously performed in one reaction step, i.e. without isolation of the intermediating compound (13), by using the corresponding excess of the oxidation agent.
In another alternative, compound of formula (4) may be also produced by condensation with a compound of formula (3.2). 
For example, condensation of bromoacetone, compound 3.2, L=Br, with p-fluorobenzenesulfinic acid salt, cyanolysis of the resulting thiol-ketone (15) and hydrolysis of the resulted cyanhydrin (16) produces a compound of formula (4). 
Compounds of formula (4) are converted to bicalutamide by an amidation reaction with the amine compound of formula (11) as described above. If desired and whenever produced in a racemic form, the compounds of formula (4) may be resolved into single enantiomers. An example is given in WO 01-34563.
In any of the above procedures, the amine compound of formula (11) may be replaced by an isocyanate compound of formula (17) in order to form the aniline derivative. For instance, the isocyanate (17) may react with the compound of formula (6) according to the following scheme: 
After condensation of (18) with p-fluorobenzenesulfinate (2), the intermediating cyclic product (19) 
is hydrolyzed, preferably in alkaline medium, to yield bicalutamide. This process can also be carried out to give bicalutamide enriched by a single enantiomer, when starting from optically active (6).
Similarly, the compound (19) may be provided by reacting the isothiocyanate (17) with a compound of formula (4).
Another reaction partner separate from the preferred compounds of formula (3) is one that converts the p-fluorobenzenesulfinate (2) into a compound of formula (20) 
wherein X is a leaving group such as halogen atom. This compound may be contacted with a suitable reaction partner, for instance with compound (21): 
to yield bicalutamide of formula (1). The compound (20) may be prepared by reaction of sodium p-fluorobenzenesulfinate with dichloroacetic acid. The compound (21) may be prepared according to EP 100172.
The invention will be further described with reference to the following non-limiting examples.